Salivary gland malignancies are rare and heterogeneous cancers of the head and neck. Mucoepidermoid and adenoid cystic carcinoma are the most common and demonstrate an unpredictable clinical course with locoregional failure and distant metastasis. Treatment is primarily surgical followed by adjuvant radiotherapy based on certain pathologic features. The role of chemotherapy, including targeted therapy, is investigational. The five year survival for high grade salivary carcinomas is approximately 40%. Given the rarity and diversity of these tumors, comprehensive genetic analysis has not been performed to date. However, there is a need for novel clinical approaches and new molecular targets are critically important for therapy development in patients with salivary gland malignancies. By performing whole genome sequencing on high grade mucoepidermoid and adenoid cystic carcinoma, this project will identify potential new avenues for therapeutic, diagnostic and prognostic intervention in salivary gland cancer. For mutational screening, we will employ whole genome sequencing on clinically annotated 20 high grade mucoepidermoid carcinoma and 20 adenoid cystic carcinoma samples. All mutations will be examined in normal DNA from the same patient to identify and confirm somatic mutations and rearrangements. The point mutations and rearrangements that are identified will then be queried in the plasma and saliva to identify their roles as biomarkers. Identification of these genetic alterations and biomarkers will likely provide potential prognostic, diagnostic and therapeutic strategies for salivary gland malignancies. PUBLIC HEALTH RELEVANCE: We will perform whole genome sequencing on twenty high grade mucoepidermoid carcinomas and twenty adenoid cystic carcinomas. We will identify key genes and pathways critical to these tumor types. Based on these findings, we will develop and validate circulating tumor DNA as a biomarker in salivary gland malignancies.